DESCRIPTION: (Principal Investigator's) The synthesis of four, naturally occurring, antitumor agents is proposed. Many of the late- stage synthetic intermediates in each of the projects will be examined for antitumor activity both here at the University of Minnesota (collaboratively) and at the National Cancer Institute. Aim I. Gigantecin (I) is a member of the rare class of Annonaceous acetogenins containing non-adjacent, bis-tetrahyfuran rings. It is an extremely potent inhibitor of in vitro tumor cell growth, reportedly having GI50's of around ten to the minus 7 and ten to the minus nine microg/mL toward human lung and breast carcinoma cell lines. Aim II. Cylindrocylophane A(II) is a C2-symmetric macrocarbocyclic compound that is a member of the only family of naturally occurring (n.n)paracyclophanes. It is cytotoxic against KB and LoVo tumor cells. Aim III. Callipeltoside A(II) is a recently reported marine natural product. The macrocyclic lactone and amino-glycoside, rare structural features for compounds isolated from marine organisms, and a unique 1- dienynyl-2-chlorocyclopropane are the novel structural features. The compound is cytotoxic toward NSCLC-N6 (non-small-cell lung carcinoma) and P388 tumor cell lines. Aim IV. The pair of isomeric 4-methylene-2-cyclohexenones IVA and IVB was recently isolated and their relative configurations determined here at the University of Minnesota. The first was previously described, without stereochemistry, in a 1996 patent from the Rhone-Poulenc Rorer company. It inhibited tubulin polymerization and had a GI50 of 1ng/mL against the doxorubicin-resistant, P388/DOX cell line. Samples of our compounds also showed remarkable levels of human tumor cell cytotoxicity in the NCI panel (e.g., GI50's for IVA of less than 100pM and IVB of less than 1nM for most cell lines and total growth inhibition (TGI) of less than 100pM and 3nM, respectively, against a breast cancer). The development of new synthetic methodology is a background theme. New aspects of the alkene metathesis reaction and a new oxidative asymmetric dearomatization reaction will be studied within the context of Aims I and IV. These methods will be generally applicable to the preparation of compounds of pharmaceutical interest.